Silencers are regions of the genome that are capable of silencing gene expression. Cancer cells show altered chromatin interactions 2, 3 including altered chromatin loops to key oncogenes such as TERT 5.īy contrast, mechanisms for gene repression are much less well understood. TFs can bind to proximal enhancers in the genome, and enhancers distal to genes can loop to gene promoters via chromatin interactions to activate gene expression 3. Gene transcription is controlled by transcription factors (TFs) that bind to enhancers and promoters to regulate genes 4. The genome is organized into large Topologically-Associated Domains (TADs) and chromatin interactions. The 3-dimensional organization of our genomes is important for gene regulation 1, 2, 3. Our results characterize H3K27me3-rich regions and their mechanisms of functioning via looping. Finally, we observe that H3K27me3-rich regions-associated genes and long-range chromatin interactions are susceptible to H3K27me3 depletion. Cells with H3K27me3-rich regions knockout also show changes in phenotype associated with cell identity, and altered xenograft tumor growth. Chromatin interactions did not change at regions with high H3K27me3, but regions with low H3K27me3 and high H3K27ac levels showed changes in chromatin interactions. H3K27me3-rich regions component removal at interaction anchors by CRISPR leads to upregulation of interacting target genes, altered H3K27me3 and H3K27ac levels at interacting regions, and altered chromatin interactions. We find that H3K27me3-rich regions are associated with chromatin interactions and interact preferentially with each other. Here we investigate the hypothesis that H3K27me3-rich regions of the genome, defined from clusters of H3K27me3 peaks, may be used to identify silencers that can regulate gene expression via proximity or looping. The mechanisms underlying gene repression and silencers are poorly understood.

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